This application is a 371 of PCT/JP00/00154 filed Jan. 14, 2000.
This invention relates to a pharmaceutical composition containing a compound having a phenolic hydroxyl group with coloring change being controlled, in detail a pharmaceutical composition comprising an anti-inflammatory agent or an antioxidant having a phenolic hydroxyl group with coloring change being controlled.
As to a compound having a phenolic hydroxyl group to be used in the present invention, a compound of the formula (I): 
wherein R1 and R2 each is independently hydrogen, low alkyl or low alkyloxy; R3 is hydrogen, low alkyl, cycloalkyl, lower alkyloxy, arylalkyloxy, heteroarylalkyloxy, lower alkylcarbonyl, arylcarbonyl, substituted or unsubstituted carbamoyl or a group of the formula: xe2x80x94(CH2)nxe2x80x94Q wherein Q is hydroxy, substituted or unsubstituted amino, aryl, heteroaryl, carboxy or low alkyloxycarbonyl; and n is an integer of 0-3, its pharmaceutically acceptable salt or a hydrate thereof (hereinafter referred to as a compound (I)) is disclosed in Japanese Patent Publication (Kokai) No. 211819/1994, and is known to be useful as an anti-inflammatory agent.
The compound (I) known as a non-steroid type anti-inflammatory agent is very useful because it is a selective inhibitor against cyclooxygenase II which does not have the side effects caused by inhibiting cyclooxygenase I.
Because the compound (I) is hardly soluble in water, it must be formulated through wet granulation process using a water-soluble high molecular compound or a surface-active agent with a high HLB value for making the surface of the compound hydrophilic in order to enhance the absorbability or solubility. But the present inventors have found that a granulation product of the compound (I) such as a wet composition in wet granulation process, a dried granule in drying process or the like, shows coloring change under a high humidity condition and a pharmaceutical composition shows coloring change, while stored under warming and humidification.
Generally, as a method for masking the coloring change of a pharmaceutical composition, a physical method such as adding a coloring agent, coating a tablet, masking a particle of a compound or the like is used. Each method is complicated to increase the production cost.
As a specific method for controlling the coloring change depending on the nature of each compound, known is a method for controlling the coloring change of a solution comprising uracil derivatives by using a metal salt of formaldehyde sulfoxyl acid, described in Japanese Patent Publication (Kokai) No. 102415/1977, or a method for controlling the coloring change of a granulation product comprising ascorbic acid by using an organic solid acid, described in Japanese Patent Publication (Kokai) No. 47121/1991. A method for controlling coloring change of a pharmaceutical composition containing a compound having a phenolic hydroxy group has not been reported.
The present invention provides a pharmaceutical composition containing a compound having a phenolic hydroxy group, in detail an anti-inflammatory agent or an antioxidant having a phenolic hydroxyl group, and in more detail a compound (I) with coloring change being controlled.